Infants infected with human immunodeficiency virus (HIV) often develop immunodeficiency and die sooner after infection than HIV-infected adults. To evaluate how viral variants may affect disease progression in human pediatric AIDS, we studied the potential of three simian immunodeficiency virus (SIV) isolates to induce Simian AIDS (SAIDS) in newborn rhesus macaques. These virus isolates were previously shown to range from pathogenic (SIVMAC251 and SIVMAC239) to non-pathogenic (SIVMAC1a11) when inoculated intravenously in juvenile and adult rhesus macaques. All six newborn macaques inoculated with pathogenic, uncloned SIVMAC251 developed persistent, high levels of cell-associated and cell-free viremia, had no detectable anti-viral antibodies, poor weight gain, and were all euthanatized with severe clinical disease and had pathologic lesions diagnostic for saids; five were euthanatized by 12 weeks after inoculation and one animal was euthanatized at 26 weeks after inoculation. Two newborns inoculated with pathogenic, molecularly cloned SIVMAC239 fared better; in spite of persistent high virus load in peripheral blood, both animals had normal weight gain, developed anti-viral antibodies, and survived for more than 32 weeks after inoculation. One of the SIVMAC239-infected neonates was euthanatized at 34 weeks after inoculation and pathologic lesions diagnostic for SAIDS; the other SIVMAC239-infected neonate remained alive with no significant clinical disease. In contrast, three newborn rhesus macaques inoculated with the non-pathogenic molecular clone, SIVMAC1a11, had transient, low-level viremia, seroconverted by 10 weeks after inoculation, had normal weight gain, and remained healthy for over one year. This study demonstrates that (i) only the uncloned pathogenic virus isolate, SIVMAC251, produced a pattern of disease in infant macaques that was accelerated, when compared with disease in older macaques, and (ii) SIV-infected neonatal macaques exhibit patterns of infection, virus load, and disease progression similar to those observed in HIV-infected children.